A second phase 3 clinical trial of Abiraterone (Zytiga) has been successfully completed for earlier stage prostate cancer in men who had not received chemotherapy. The trial has been halted early due to positive results so that the placebo arm could offered treatment with Abiraterone.
In one of those situations when actual clinical practice precedes the normal drug development process a recent announcement from Janssen Research & Development, LLC (Johnson & Johnson) informs that they have un-blinded their Phase 3 study, COU-AA-302, which clearly demonstrates that Zytiga (abiraterone acetate), when taken with prednisone, is effective in treating both mildly symptomatic or asymptomatic men who have metastatic castration-resistant prostate cancer (CRPC) and have not yet had chemotherapy.
The U.S Food and Drug Administration (FDA) approved Zytiga in 2011 for men post chemotherapy failure. According to William N. Hait, MD, PhD, from Global Head, Janssen R&D,
“Since its first approval in the U.S in 2011, Zytiga has been approved in 39 additional countries, many thousands of men have received treatment with it, and it is quickly becoming one of the cornerstones of our oncology offerings.”
The trial, COU-AA-302 which is a double-blind, randomized, international, placebo-controlled study, involved 1,088 men who were given either Zytiga at a dosage of 1,000 mg once a day, as well as prednisone at 5mg twice a day, or a prednisone 5mg twice a day, as well as a placebo.
After analyzing the early data it was recommended by The Independent Data Monitoring Committee (IDMC) that the study be un-blinded and men in the control arm be offeed Zytiga. The Committee made their recommendation after they found the study reached statistical significance on a primary endpoint which was R-PFS and on all secondary endpoints as well as a strong trend for overall survival, all of which constituted compelling evidence of clinical benefit. The actual survival data will continue to mature, however the data will be clouded because of the crossover of men in the placebo arm who will now get Zytiga.
The results from the study have not yet been published, but they will be presented at a medical meeting in the near future, as well as be published in a peer-reviewed journal.
Since the side effect profile of Zytiga is less than chemotherapy, many clinicians have already been using Zytiga with men who have not yet had chemotherapy. The surprise is that most insurance companies have paid for this “off label” treatment. With this new data hopefully those companies that have not been willing to pay for early Zytiga will re-evaluate their position.
Tuesday, 27 March 2012
Sunday, 25 March 2012
Mechanism of Zytiga
Zytiga works by inhibiting the enzyme CYP17 which blocks androgen production in the body. Here is a picture of Zytiga binding into the active site of CYP17. There is a very precise moloecular fit of Zytiga into the CYP17 enzyme which explains why it is so potent at inhibiting this enzyme.
Discovery of Abiraterone
Abiraterone was first discovered by Professor Gerry Potter in November 1990 in the CRUK Centre for Cancer Therapeutics at the Institute of Cancer Research in London. The picture below shows Gerry Potter carrying out the first synthesis of abiraterone in the laboratory. This process was then scaled up to make killogram quantities. Abiraterone was designed to inhibit the enzyme CYP17 which prevents the production of androgens in the body. Prostate cancer is dependent upon androgens for its growth and replication, so switching off the supply of androgens with Abiraterone causes regression of prostate tumours.
New Drugs for the Treatment of Prostate Cancer
There are a lot of new drugs emerging for prostate cancer and this article describes whats hot in this area. Some of the new drugs are changing oncology practice and are setting new paradigms in pain relief.
Here are the new front runners in the treatment of prostate cancer:
Abiraterone (Zytiga, Johnson & Johnson)
This an oral drug that is an anti hormonal agent. Zytiga blocks production of androgens in the body. Zytiga does this by inhibiting the enzyme CYP17 that is responsible for androgen biosynthesis. Zytiga inhibits CYP17 and blocks all androgen production and so works even when other anti hormonal strategies have failed. It should be seen as the last line in hormonal therapy. If patients relapse on Zytiga then the cancer is truly hormone independent prostate cancer.
Initial phase III trials on Zytiga showed an 80% response rate in men with metastatic castrate resistant prosatate cancer who had been given chemotherapy. Therefore there are 20% of men who will not respond to Zytiga. Results of these controlled phase III trials in a cohort of 1,200 men worldwide showed that Zytiga significantly prolonged overall survival (OS) in patients with metastatic castration resistant prostate cancer (CRPC) who had progressed on docetaxel-based chemotherapy, and the survival benefit of 4 months was consistent across all pre-specified subgroups. These trials were stopped early due to the favourable results so that the placebo arm could receive Zytiga, and it is not yet possible to determine the real long term survival benefits of this treatment. From the first Phase III trials there are men taking Zytiga that have been alive for 4 years.
Zytiga should be considered as a new standard of care, said lead author Howard Scher, MD, chief of the genitourinary oncology service for urology and prostate cancers at Memorial Sloan-Kettering Cancer Center in New York City.
The first phase III study enrolled 1200 patients with metastatic CRPC who failed on 1 or 2 previous lines of chemotherapy (at least one with docetaxel). Patients were randomized to Zytiga 1000 mg plus prednisone 5 mg twice daily versus placebo plus prednisone. The two arms were well balanced for demographic and disease characteristics.
A second phase III study of Zytiga in men who had not received chemotherapy. This trial has also been stopped early due to favourable results and the placebo arm are now receiving Zytiga. Early indications showed benefits such as reduction in bone pain and extension of survival time.
Zytiga achieved significantly superior OS versus placebo: a median of 14.8 months versus 10.9 months, representing a 35% relative risk reduction of mortality (P <.0001). The survival benefit was consistent across subgroups in a pre-planned analysis stratified for number of lines of prior chemotherapy, performance status, pain scores, and radiographic progression-free survival (PFS). Total and confirmed PSA response rates were also superior in the abiraterone-treated arm.
Adverse events of all grades and of grades 3 and 4 were similar between the two treatment arms and were manageable.
Bone pain reduction was noted in many cases, and quality of life enhanced due to increased mobility which are further features of this agent. Many men came off morphine while taking Zytiga.
Oliver Sartor, MD, said, "This is a game-changer. To me this will change practice." Dr Sartor is director of the prostate cancer program at Tulane University School of Medicine in New Orleans, LA.
Salvestrol Platinum (Q40, SNP)
This is a new type of approach which is a food supplement that contains salvestrols aimed at targetting the tumour and the metastasis. Salvestrol Q40 is a smart prodrug that targets cancer cells and destroys them. This has been formulated together with 3 other salvestrols for maximum effect in the supplement Salvestrol Platinum. Salvestrols are activated by the CYP1B1 enzyme in tumours to release a stream of toxic metabolite inside the tumour cells specifically targetting the tumour cells and the metastasis. The metabolite salvestrol Q50 is an inhibitor of many tyrosine kinase enzymes implicated in cancer, so salvestrols are able to act as a natural pan-kinase inhibitor prodrug. Salvestrol Platinum exhibits remarkable antitumour effects and these have been published as a series of case studies. Two types of response were seen. Fast reponders and slow responders. The fast responders typically observe the tumour shrinking to half its size within 1 month and are all clear by 3 months. Others take much longer and required high dose salvestrols (12,000 points per day) with only partial responses observed after 6 months but the disease contained after a year. Salvestrol aslo achieved resolution of bone metastases and associated pain. These studies were was based on case studies. Of these about 50% had progression of disease following chemotherapy, 78% had bone metastasis, 50% had significant pain, and 37% required narcotics for pain.
Resolution of bone metastasis was observed in 85% of 62 patients with available bone scans; 8 additional patients had stable disease after 12 months. Of 43 evaluable patients with bone metastases and bone pain, 60% reported improvement in pain at 6 and 12 weeks of treatment with salvestrol. Of 33 evaluable patients who required narcotics for bone pain, 64% reported improvement in pain at 6 or 12 weeks, and 46% decreased or discontinued usage of narcotics.
According to preliminary data, the drug appears to have pronounced anti-tumor effects. Side effects included stomach upset (5% ), diarrhea (5%), decreased appetite (20%), hypertension (1%), and skin rash (1%).
Additional clinical studies are planned. Several experts who were not involved in this study were enthusiastic about what appears to be "remarkable" and "unprecedented" antitumour effects.
Cabozantinib (XL 184, Exelixis)
This is a new type of drug aimed at targetting metastasis. Cabozantinib is an inhibitor of Met kinase and VEGFR2.
In phase II clinical trials Cabozantinib (XL 184) exhibited exciting antimetastatic activity and achieved resolution of bone metastases and associated pain. According to preliminary data, the drug also appears to have an anti-tumour effect. A phase I trial of Zytiga in combination with Cabozantinib is underway.
Degarelix (Firmagon, Ferring)
This is an injectable drug which is a new type of LHRH antagonist which works on a similar principle to the LHRH agonists Zoladex and Luperon but is more direct in its action as an antagonist of LHRH.
An open-label extension study of a phase III pivotal study found that degarelix slowed prostate-specific antigen (PSA) progression significantly in patients with prostate cancer treated with Luperon (leuprolide) for 12 months and then switched to Degarelix. This benefit was consistent with the primary results of the phase 3 trial showing that degarelix was superior to leuoprolide in the rate of androgen suppression, PSA suppression, risk of PSA failure or death, and reduced levels of a biomarker associated with metastatic death. Data from the open-label extension study also showed that Degarelix was associated with a significant increase in the interval before 25% of patients experienced PSA failure or death. Mean follow-up was 27.5 months.
Lead author Neil Shore MD, of the Carolina Research Center in Myrtle Beach, South Carolina, said that the data support the use of degarelix as first-line androgen deprivation therapy based on the durability of the significant progression-free survival benefit that emerged when degarelix was compared with leuprolide in the randomized phase 3 trial and was sustained in the open-label phase.
The data presented by Dr Shore focused on the group of patients treated with Degarelix 80 mg, which is the approved dose. Progression of PSA was slowed in all men in the extension phase as well as a subgroup of men with PSA values >20 ng/mL (P = .003)
Xtandi (Enzalutamide, MDV -3100) (Medivation/Astellas Pharma Inc.)
This is an oral drug which is an analogue of Casodex (bicalutamide)
MDV3100 achieved durable antitumor activity as reflected by median times to PSA progression and radiographic progression in men with advanced prostate cancer. These updated results at 42 months of follow-up of a phase I-II study confirmed interim results of the trial showing antitumor activity with this agent in patients who developed resistance to casodex (bicalutamide) or other standard anti-androgen treatments.
The phase I-II trial enrolled 140 men with progressive disease between July 2007 and December 2008. Of those, 18 remained on active treatment at the time of ASCO GU. Median time to PSA progression according to protocol-specified criteria had not yet been reached in 65 chemotherapy-naïve patients and was 316 days in 75 patients post-chemotherapy. Median time to radiographic progression was 392 days and 175 days, respectively. Circulating tumor cell counts were available for 128 patients; of these, 70 of 77 (91%) with favorable pre-treatment counts remained favorable post-treatment, and 15 of 51 patients (49%) converted from unfavorable to favorable post-treatment counts.
The drug is currently under evaluation in two randomized, placebo-controlled phase III trials: AFFIRM and PREVAIL. So far 5 seizures have been observed raising questions over its cardiotoxicity. Similar drugs such as Vioxx were withdrawn from the market due to cardiotoxicity. MDV3100 is an antiandrogen that is described as the first triple-acting, oral androgen receptor antagonist being developed for the treatment of advanced prostate cancer and provides more complete suppression of the androgen receptor pathway than casodex (bicalutamide), the most commonly-used anti-androgen, according to the company's news releases. Unlike abiraterone, no steroids are necessary with MDV3100.
Here are the new front runners in the treatment of prostate cancer:
Abiraterone (Zytiga, Johnson & Johnson)
This an oral drug that is an anti hormonal agent. Zytiga blocks production of androgens in the body. Zytiga does this by inhibiting the enzyme CYP17 that is responsible for androgen biosynthesis. Zytiga inhibits CYP17 and blocks all androgen production and so works even when other anti hormonal strategies have failed. It should be seen as the last line in hormonal therapy. If patients relapse on Zytiga then the cancer is truly hormone independent prostate cancer.
Initial phase III trials on Zytiga showed an 80% response rate in men with metastatic castrate resistant prosatate cancer who had been given chemotherapy. Therefore there are 20% of men who will not respond to Zytiga. Results of these controlled phase III trials in a cohort of 1,200 men worldwide showed that Zytiga significantly prolonged overall survival (OS) in patients with metastatic castration resistant prostate cancer (CRPC) who had progressed on docetaxel-based chemotherapy, and the survival benefit of 4 months was consistent across all pre-specified subgroups. These trials were stopped early due to the favourable results so that the placebo arm could receive Zytiga, and it is not yet possible to determine the real long term survival benefits of this treatment. From the first Phase III trials there are men taking Zytiga that have been alive for 4 years.
Zytiga should be considered as a new standard of care, said lead author Howard Scher, MD, chief of the genitourinary oncology service for urology and prostate cancers at Memorial Sloan-Kettering Cancer Center in New York City.
The first phase III study enrolled 1200 patients with metastatic CRPC who failed on 1 or 2 previous lines of chemotherapy (at least one with docetaxel). Patients were randomized to Zytiga 1000 mg plus prednisone 5 mg twice daily versus placebo plus prednisone. The two arms were well balanced for demographic and disease characteristics.
A second phase III study of Zytiga in men who had not received chemotherapy. This trial has also been stopped early due to favourable results and the placebo arm are now receiving Zytiga. Early indications showed benefits such as reduction in bone pain and extension of survival time.
Zytiga achieved significantly superior OS versus placebo: a median of 14.8 months versus 10.9 months, representing a 35% relative risk reduction of mortality (P <.0001). The survival benefit was consistent across subgroups in a pre-planned analysis stratified for number of lines of prior chemotherapy, performance status, pain scores, and radiographic progression-free survival (PFS). Total and confirmed PSA response rates were also superior in the abiraterone-treated arm.
Adverse events of all grades and of grades 3 and 4 were similar between the two treatment arms and were manageable.
Bone pain reduction was noted in many cases, and quality of life enhanced due to increased mobility which are further features of this agent. Many men came off morphine while taking Zytiga.
Oliver Sartor, MD, said, "This is a game-changer. To me this will change practice." Dr Sartor is director of the prostate cancer program at Tulane University School of Medicine in New Orleans, LA.
Salvestrol Platinum (Q40, SNP)
This is a new type of approach which is a food supplement that contains salvestrols aimed at targetting the tumour and the metastasis. Salvestrol Q40 is a smart prodrug that targets cancer cells and destroys them. This has been formulated together with 3 other salvestrols for maximum effect in the supplement Salvestrol Platinum. Salvestrols are activated by the CYP1B1 enzyme in tumours to release a stream of toxic metabolite inside the tumour cells specifically targetting the tumour cells and the metastasis. The metabolite salvestrol Q50 is an inhibitor of many tyrosine kinase enzymes implicated in cancer, so salvestrols are able to act as a natural pan-kinase inhibitor prodrug. Salvestrol Platinum exhibits remarkable antitumour effects and these have been published as a series of case studies. Two types of response were seen. Fast reponders and slow responders. The fast responders typically observe the tumour shrinking to half its size within 1 month and are all clear by 3 months. Others take much longer and required high dose salvestrols (12,000 points per day) with only partial responses observed after 6 months but the disease contained after a year. Salvestrol aslo achieved resolution of bone metastases and associated pain. These studies were was based on case studies. Of these about 50% had progression of disease following chemotherapy, 78% had bone metastasis, 50% had significant pain, and 37% required narcotics for pain.
Resolution of bone metastasis was observed in 85% of 62 patients with available bone scans; 8 additional patients had stable disease after 12 months. Of 43 evaluable patients with bone metastases and bone pain, 60% reported improvement in pain at 6 and 12 weeks of treatment with salvestrol. Of 33 evaluable patients who required narcotics for bone pain, 64% reported improvement in pain at 6 or 12 weeks, and 46% decreased or discontinued usage of narcotics.
According to preliminary data, the drug appears to have pronounced anti-tumor effects. Side effects included stomach upset (5% ), diarrhea (5%), decreased appetite (20%), hypertension (1%), and skin rash (1%).
Additional clinical studies are planned. Several experts who were not involved in this study were enthusiastic about what appears to be "remarkable" and "unprecedented" antitumour effects.
Cabozantinib (XL 184, Exelixis)
This is a new type of drug aimed at targetting metastasis. Cabozantinib is an inhibitor of Met kinase and VEGFR2.
In phase II clinical trials Cabozantinib (XL 184) exhibited exciting antimetastatic activity and achieved resolution of bone metastases and associated pain. According to preliminary data, the drug also appears to have an anti-tumour effect. A phase I trial of Zytiga in combination with Cabozantinib is underway.
Degarelix (Firmagon, Ferring)
This is an injectable drug which is a new type of LHRH antagonist which works on a similar principle to the LHRH agonists Zoladex and Luperon but is more direct in its action as an antagonist of LHRH.
An open-label extension study of a phase III pivotal study found that degarelix slowed prostate-specific antigen (PSA) progression significantly in patients with prostate cancer treated with Luperon (leuprolide) for 12 months and then switched to Degarelix. This benefit was consistent with the primary results of the phase 3 trial showing that degarelix was superior to leuoprolide in the rate of androgen suppression, PSA suppression, risk of PSA failure or death, and reduced levels of a biomarker associated with metastatic death. Data from the open-label extension study also showed that Degarelix was associated with a significant increase in the interval before 25% of patients experienced PSA failure or death. Mean follow-up was 27.5 months.
Lead author Neil Shore MD, of the Carolina Research Center in Myrtle Beach, South Carolina, said that the data support the use of degarelix as first-line androgen deprivation therapy based on the durability of the significant progression-free survival benefit that emerged when degarelix was compared with leuprolide in the randomized phase 3 trial and was sustained in the open-label phase.
The data presented by Dr Shore focused on the group of patients treated with Degarelix 80 mg, which is the approved dose. Progression of PSA was slowed in all men in the extension phase as well as a subgroup of men with PSA values >20 ng/mL (P = .003)
Xtandi (Enzalutamide, MDV -3100) (Medivation/Astellas Pharma Inc.)
This is an oral drug which is an analogue of Casodex (bicalutamide)
MDV3100 achieved durable antitumor activity as reflected by median times to PSA progression and radiographic progression in men with advanced prostate cancer. These updated results at 42 months of follow-up of a phase I-II study confirmed interim results of the trial showing antitumor activity with this agent in patients who developed resistance to casodex (bicalutamide) or other standard anti-androgen treatments.
The phase I-II trial enrolled 140 men with progressive disease between July 2007 and December 2008. Of those, 18 remained on active treatment at the time of ASCO GU. Median time to PSA progression according to protocol-specified criteria had not yet been reached in 65 chemotherapy-naïve patients and was 316 days in 75 patients post-chemotherapy. Median time to radiographic progression was 392 days and 175 days, respectively. Circulating tumor cell counts were available for 128 patients; of these, 70 of 77 (91%) with favorable pre-treatment counts remained favorable post-treatment, and 15 of 51 patients (49%) converted from unfavorable to favorable post-treatment counts.
The drug is currently under evaluation in two randomized, placebo-controlled phase III trials: AFFIRM and PREVAIL. So far 5 seizures have been observed raising questions over its cardiotoxicity. Similar drugs such as Vioxx were withdrawn from the market due to cardiotoxicity. MDV3100 is an antiandrogen that is described as the first triple-acting, oral androgen receptor antagonist being developed for the treatment of advanced prostate cancer and provides more complete suppression of the androgen receptor pathway than casodex (bicalutamide), the most commonly-used anti-androgen, according to the company's news releases. Unlike abiraterone, no steroids are necessary with MDV3100.
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